Brian Arey: Discovering Signaling Bias at the FSH Receptor

Biased signaling - the idea that a single receptor can preferentially activate one downstream pathway over another depending on how it is engaged - is now a central concept in GPCR pharmacology and drug design. But for the researcher who first encountered it not as a theory but as an anomalous bell-shaped dose-response curve in an FSH receptor assay, it arrived as a problem that needed explaining. Brian Arey, Director of Mechanistic Pharmacology at Bristol-Myers Squibb, traces the origins of that discovery to a glycosylation difference between pituitary-purified and insect-cell-expressed FSH - a difference that turned out to encode physiologically distinct signaling outputs. The broader argument Arey has spent his career developing is that biased signaling is not a GPCR-specific phenomenon but an evolutionarily conserved principle present across all receptor classes. That argument eventually became a book, co-authored with Terry Kenakin, that Arey dedicated to his children - not because they are scientists, but because he wanted them to understand what he spent his life doing and why it mattered.

ABOUT THE GUEST

Brian Arey is Director of Mechanistic Pharmacology within the Discovery and Optimization organization at Bristol-Myers Squibb, where he leads research spanning GPCR pharmacology, enzymology, and protein homeostasis pathways. A physiologist by training, he completed his doctoral work on circadian regulation of prolactin secretion at Florida State University before postdoctoral research at Northwestern, and has spent over 25 years in pharmaceutical drug discovery across Wyeth and BMS. His early work at Wyeth's Women's Health Research Institute produced foundational observations on biased signaling at the FSH receptor, which were among the first experimental demonstrations that a GPCR could signal through parallel G protein pathways in a ligand-dependent manner. He is the author of a 2014 book on evolutionarily conserved receptor signaling, co-written with Terry Kenakin and published through Elsevier.

SCIENTIFIC THEMES OF THE CONVERSATION

1. Biased signaling at glycoprotein hormone receptors - the experimental origin
   

2. Glycosylation isoforms as physiological regulators of differential receptor signaling
   

3. Evolutionary conservation of biased receptor function across receptor classes
   

4. The physiologist's approach to mechanistic drug discovery
   

5. The erosion of pharmacology training in pharmaceutical research - and why it matters
   

6. Career navigation across academia, industry, and the blurring boundary between them

KEY INSIGHTS FROM THE CONVERSATION

The bell-shaped curve was a hypothesis, not an artifact

When insect-cell-expressed FSH produced a bell-shaped dose-response curve instead of a sigmoidal one, the obvious interpretation was contamination or a production problem. Arey treated it as a signal. The glycosylation difference between the recombinant material and pituitary-purified FSH had altered the receptor's downstream signaling profile - and the bell shape was the read-out. It took a pertussis toxin experiment, borrowed conceptually from Tom Burris's dopamine receptor work, to demonstrate that FSH receptor was signaling through both Gs and Gi simultaneously, and that the two glycoforms were biasing the system differently.

Forty years of unresolved biology had a signaling answer

The existence of multiple glycosylated isoforms of FSH, LH, and other glycoprotein hormones had been recognized for decades, but their physiological significance was not understood. Arey's data offered a functional explanation: different glycoforms stabilize different receptor conformations, which recruit different intracellular effectors with different affinities, driving different physiological outcomes in target cells. What had looked like biochemical noise in circulating hormone pools was, in this framework, a mechanism for fine-tuned signaling control.

If the controls are right, the data has to be trusted

When a substantial portion of the literature responded to Arey's published data by calling it wrong, he called his graduate advisor. The advice he received - that if all controls have been run appropriately and the result still holds, you have to have confidence in your data - has remained his operating principle for three decades. That conviction did not resolve the argument quickly. The field took nearly a decade to come around. But the data held.

Biased signaling is not a GPCR specialty - it is a conserved principle

The central argument of Arey's 2014 book is that the bimodal structure of receptor signaling - a ligand-binding pocket with one inherent affinity, and a cytoplasmic effector-binding pocket with its own independent affinity, both modulated by the conformational state the ligand stabilizes - is not unique to GPCRs. The same logic applies to cytokine receptors, nuclear hormone receptors, and receptor tyrosine kinases. Arey arrived at this hypothesis in the mid-1990s, before the structural and mechanistic data existed to support it, and spent years watching the field gradually produce that evidence.

Techniques are tools in a toolbox - not endpoints

One of the formative intellectual influences Arey credits from his graduate training is the principle that no technology is intrinsically interesting - it is only interesting insofar as it can answer a scientific question. That orientation shapes how he runs his team at BMS: a healthy skepticism toward established methods, including antibody-based assays that he views as 50-year-old technology capable of improvement, and a standing question of whether the current tool is actually capturing the biology being studied.

Drug discovery needs modulators more than it needs hammers

Arey's philosophy of drug discovery is grounded in a view of human physiology as inherently variable - shaped by evolution, divergent across populations, and rarely susceptible to single-target solutions. He argues for a therapeutic strategy built around modulators that can be combined, rather than single agents designed to dominate a pathway. That argument is not abstract: it is the conclusion of someone who has watched large programs fail to find silver bullets in multifactorial diseases for 25 years.

EPISODE TIMELINE

Timestamps are AI-generated from the transcript and may not perfectly reflect final edited audio. Verify against the published episode before using for navigation.

• 00:00 Introduction

• 01:48 Career overview - 25 years in drug discovery at Wyeth and BMS

• 06:03 Origin story - glassware, the first binding assay, and the decision not to become a physician

• 11:54 Graduate school - independently discovering a circadian rhythm regulating prolactin secretion still cited 30 years later

• 17:57 Leaving academia for Wyeth - a two-week decision, $18,000 a year, and the door that closed behind it

• 19:55 The FSH receptor anomaly - how a production shortcut produced the first experimental evidence of biased GPCR signaling

• 23:40 When the literature called the data wrong - holding the line for nearly a decade

• 30:41 The physiologist's lens - why Arey has never chased the trending field

• 35:00 Science, family, and the years he was a single father of two young children

• 40:35 Writing the book with Kenakin - the argument that biased signaling is evolutionarily conserved, and why he chose a book over a review

• 48:09 Dinner with Martin Rodbell - drawing the FSH data on a napkin and hearing "I'm not surprised"

• 53:07 Advice for scientists - follow the data, trust your controls, stay humble, give back

• 01:01:55 What pharmacologists bring to drug discovery that nobody else does

SELECTED QUOTES

About this episode

Brian Arey is Senior Director of Mechanistic Pharmacology within Leads Discovery and Optimization at Bristol-Myers Squibb Co. in Lawrenceville, NJ.

He obtained both his MS and Ph.D. in Neuroendocrine Physiology at Florida State University before completing his postdoctoral training at Northwestern University. He then moved to work in the pharmaceutical industry where he has held positions of increasing responsibility. He currently leads a team that provides a mechanistic understanding of small molecule drug candidates across the entire portfolio of BMS. Brian has contributed to the discovery or development of 5 marketed drugs through his work spanning molecular, biochemical, cellular, and in vivo assessment of drug candidates in many different physiological systems.

Dr. Arey’s laboratory discovered the first described synthetic agonists and antagonists of the FSHR and has been an early champion of signaling bias as a physiological mechanism of gonadotropin action. He continues to pioneer in drug discovery studying GPCRs and other target classes. His recently published book on signaling bias, Biased Signaling in Physiology, Pharmacology, and Therapeutics is available on Amazon.

I sat down with Brian to chat about GPCRs, working in the industry, and being a leader. This is part 1 of our conversation.

Dr. Brian Arey on the web

• LinkedIn

• ResearchGate

• Pubmed

• Dr. GPCR Ecosystem